The Ki-67 index is an established prognostic factor in gastrointestinal neuroendocrine tumors (GI-NETs) and defines tumor grade. It is currently estimated by microscopically examining tumor tissue single-immunostained (SS) for Ki-67 and counting the number of Ki-67-positive and Ki-67-negative tumor cells within a subjectively picked hot-spot. Intraobserver variability in this procedure as well as difficulty in distinguishing tumor from non-tumor cells can lead to inaccurate Ki-67 indices and possibly incorrect tumor grades. We introduce two computational tools that utilize Ki-67 and synaptophysin double-immunostained (DS) slides to improve the accuracy of Ki-67 index quantitation in GI-NETs: (1) Synaptophysin-KI-Estimator (SKIE), a pipeline automating Ki-67 index quantitation via whole-slide image (WSI) analysis and (2) deep-SKIE, a deep learner-based approach where a Ki-67 index heatmap is generated throughout the tumor. Ki-67 indices for 50 GI-NETs were quantitated using SKIE and compared with DS slide assessments by three pathologists using a microscope and a fourth pathologist via manually ticking off each cell, the latter of which was deemed the gold standard (GS). Compared to the GS, SKIE achieved a grading accuracy of 90% and substantial agreement (linear-weighted Cohen’s kappa 0.62). Using DS WSIs, deep-SKIE displayed a training, validation, and testing accuracy of 98.4%, 90.9%, and 91.0%, respectively, significantly higher than using SS WSIs. Since DS slides are not standard clinical practice, we also integrated a cycle generative adversarial network into our pipeline to transform SS into DS WSIs. The proposed methods can improve accuracy and potentially save a significant amount of time if implemented into clinical practice.
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